BACKGROUND

Armed violence is a major public health and humanitarian problem in Iraq. In this descriptive statistical analysis we aimed to describe for the first time Iraqi civilian deaths caused by perpetrators of armed violence during the first 5 years of the Iraq war: over time; by weapon used; by region (governorate); and by victim demographics.

RESULTS

We analyzed the Iraq Body Count database of 92,614 Iraqi civilian direct deaths from armed violence occurring from March 20, 2003 through March 19, 2008, of which Unknown perpetrators caused 74% of deaths (n = 68,396), Coalition forces 12% (n = 11,516), and Anti-Coalition forces 11% (n = 9,954). We analyzed the subset of 60,481 civilian deaths from 14,196 short-duration events of lethal violence to link individual civilian deaths to events involving perpetrators and their methods. One-third of civilian violent death was from extrajudicial executions by Unknown perpetrators; quadratic regression shows these deaths progressively and disproportionately increased as deaths from other forms of violence increased across Iraq's governorates. The highest average number of civilians killed per event in which a civilian died were in Unknown perpetrator suicide bombings targeting civilians (19 per lethal event) and Coalition aerial bombings (17 per lethal event). In temporal analysis, numbers of civilian deaths from Coalition air attacks, and woman and child deaths from Coalition forces, peaked during the invasion. We applied a Woman and Child "Dirty War Index" (DWI), measuring the proportion of women and children among civilian deaths of known demographic status, to the 22,066 civilian victims identified as men, women, or children to indicate relatively indiscriminate perpetrator effects. DWI findings suggest the most indiscriminate effects on women and children were from Unknown perpetrators using mortar fire (DWI = 79) and nonsuicide vehicle bombs (DWI = 54) and from Coalition air attacks (DWI = 69). Coalition forces had higher Woman and Child DWIs than Anti-Coalition forces, with no evidence of decrease over 2003-2008, for all weapons combined and for small arms gunfire, specifically.

CONCLUSIONS

Most Iraqi civilian violent deaths during 2003-2008 of the Iraq war were inflicted by Unknown perpetrators, primarily through extrajudicial executions that disproportionately increased in regions with greater numbers of violent deaths. Unknown perpetrators using suicide bombs, vehicle bombs, and mortars had highly lethal and indiscriminate effects on the Iraqi civilians they targeted. Deaths caused by Coalition forces of Iraqi civilians, women, and children peaked during the invasion period, with relatively indiscriminate effects from aerial weapons. Please see later in the article for the Editors' Summary.

Analogical mapping is a core process in human cognition. A number of valuable computational models of analogy have been created, capturing aspects of how people compare representations, retrieve potential analogs from memory, and learn from the results. In the past 25 years, this area has progressed rapidly, fueled by strong collaboration between psychologists and Artificial Intelligence (AI) scientists, with contributions from linguists and philosophers as well. There is now considerable consensus regarding the constraints governing the mapping process. However, computational models still differ in their focus, with some aimed at capturing the range of analogical phenomena at the cognitive level and others aimed at modeling how analogical processes might be implemented in neural systems. Some recent work has focused on modeling interactions between analogy and other processes, and on modeling analogy as a part of larger cognitive systems. WIREs Cogni Sci 2011 2 266-276 DOI: 10.1002/wcs.105 For further resources related to this article, please visit the WIREs website.

OBJECTIVE

To identify, categorize, and assess critical incidents of nonadherence to standard precautions.

METHODS

Qualitative and quantitative analysis of a written, mail-out survey.

METHODS

Community hospitals.

METHODS

Statewide stratified random sample of community hospital-based health care workers at risk for blood exposure. MAIN VARIABLE: Responses to the question: "Think of an incident during the past year when you didn't adhere to universal precautions. Please describe the situation and why you didn't adhere."

RESULTS

Reasons given for not using precautions included: belief that stopping to use standard precautions would have put the patient at risk (22%); using precautions would have interfered with patient care (20%); precautions were not warranted in a specific situation (14%); did not anticipate the potential for exposure (14%); and high job demands that had caused respondent to be in a hurry (11%). Less often, equipment was not available (7%), respondent forgot (6%), respondent thought that the patient did not pose a risk (4%), or the available equipment was not effective (3%). In terms of overall exposure rates, 34% of those who described an incident had experienced a sharps injury during the previous 3 months and 42% had experienced a mucocutaneous exposure. In terms of overall nonadherence, 44% wore gloves less than 100% of the time, while 61% washed their hands less than 100% of the time. Needlestick injuries were lowest among those who had forgotten to use precautions, while mucocutaneous exposures were highest among those who had not anticipated potential exposure while performing the task. Failure to wear gloves routinely was highest among those who said that following precautions interfered with their ability to provide care and among those who believed a particular patient to be low risk; failure to wash hands routinely was also highest among the latter group and lowest among those who said necessary equipment was not available.

CONCLUSIONS

Using specific information about local incidents of nonadherence to standard precautions may enhance training, especially if the program identifies incidents of unanticipated exposure and helps workers plan for them in the future. Closer examination of job demands and responsibilities that interfere with standard precautions may increase the likelihood of adherence.

OBJECTIVE

ESTRO has set up a Quality Assurance network (EQUAL) to check the dose delivered on axis in reference and non-reference conditions for external radiotherapy. The external audits covered by the network are based on measurements made with mailed thermoluminescent dosimeters (TLD).

METHODS

The TLD consist of LiF powder type DTL 937 read with a PCL 3 automatic TLD reader. The participating centres are instructed to deliver to the TLDs absorbed doses of 2 Gy calculated with the Treatment Planning System used in clinical routine. A maximum of three photon energies by participating centre have been checked with 10 on-axis points per beam. The quantities checked include the reference beam output, beam output variation with collimator opening, depth dose data and wedge transmission factor.

RESULTS

During the 1998 EQUAL programme 102 centres have been checked corresponding to 235 beams (28 (60)Co beams and 207 X-ray beams). About 3% of the outputs in reference conditions show deviations outside tolerance level >>+/-5%). A similar rate of deviation is noted for the percentage depth doses. A rate of deviation (6%) has been observed for the beam output variation (open and wedged beams) and the wedge transmission factor. The analysis of the results shows that for 24 out of the 102 centres, a deviation outside tolerance level is observed at least in one point, mainly for the large and rectangular field sizes and for the wedged beams.

CONCLUSIONS

The results for the EQUAL programme show the importance of a quality assurance network in Radiotherapy especially for the non reference points even if they are only located on the beam axis (In order to participate in this network, please contact EQUAL secretariat or download the attached application form ESTRO web site: Dr I.H. Ferreira or Mrs Aline Mechet, EQUAL-ESTRO, Physics Department, Institut Gustave-Roussy 39 Rue Camille Desmoulins, F-94805 Villejuif Cedex, France. e-mail:equal@igr.fr or http://www.estro.be/).

Developing B and T cells assemble gene segments in order to create the variable regions of immunoglobulin and T-cell receptors required by our adaptive immune response. The chemistry of this recombination pathway requires a specific nuclease and a more general repair pathway for double-strand breaks. A complex of the recombination-activating gene 1 (RAG1) and RAG2 proteins provides the nuclease activity. In fact, RAG1 and RAG2 probably coordinate many steps involving the coding and signaling DNA sequences. Studies using deletion and truncation mutants of the RAG proteins demonstrate that each of these contain a functional core region, representing about two-thirds of the polypeptides. While the core regions are sufficient to catalyze recombination in test systems, the full-length proteins seem to show more complicated behaviors in vivo. A plausible explanation is that regions outside the core help in the proper regulation of recombination. The non-core region of RAG1 has been found to contain a ubiquitin ligase. Regulatory functions may contribute to autoregulation of the proteins involved, fidelity of the reaction, protection of the cell from translocations, coordination of recombination with the cell cycle, and possibly modification of the chromatin structure of target DNA.

Psoriasis vulgaris is a common and chronic inflammatory skin disease which has the potential to significantly reduce the quality of life in severely affected patients. The incidence of psoriasis in Western industrialized countries ranges from 1.5 to 2%. Despite the large variety of treatment options available, patient surveys have revealed insufficient satisfaction with the efficacy of available treatments and a high rate of medication non-compliance. To optimize the treatment of psoriasis in Germany, the Deutsche Dermatologische Gesellschaft and the Berufsverband Deutscher Dermatologen (BVDD) have initiated a project to develop evidence-based guidelines for the management of psoriasis. The guidelines focus on induction therapy in cases of mild, moderate, and severe plaque-type psoriasis in adults. The short version of the guidelines reported here consist of a series of therapeutic recommendations that are based on a systematic literature search and subsequent discussion with experts in the field; they have been approved by a team of dermatology experts. In addition to the therapeutic recommendations provided in this short version, the full version of the guidelines includes information on contraindications, adverse events, drug interactions, practicality, and costs as well as detailed information on how best to apply the treatments described (for full version, please see Nast et al., JDDG, Suppl 2:S1-S126, 2006; or http://www.psoriasis-leitlinie.de ).

OBJECTIVE

ISRs remain a major issue in the endovascular management of ICAD, requiring retreatment by reangioplasty. The aim of the present study was to evaluate the technical feasibility, safety, and efficiency of the novel DEBs for neurovascular ISRs.

METHODS

Fifty-one patients (median age, 67 years; age range, 34-82 years; male/female ratio, 37:14) underwent 63 balloon dilation procedures for ISRs in intracranial stented arterial segments between November 2007 and August 2010 in a single center. Of the 63 procedures, 20 (32%) were performed by using a conventional balloon and 43 (68%), by using a paclitaxel-eluting balloon (SeQuent Please). Angiographic and clinical follow-up was performed at 6 and 12 weeks, 6 and 12 months, and yearly thereafter. Technical success rate, periprocedural complications, occurrence of recurrent ischemic symptoms, and the development of a recurrent ISR after reangioplasty were analyzed.

RESULTS

Technical success, defined as <50% residual stenosis was achieved in all cases (100%), with failure of the DEB treatment in 6% of the attempts; those lesions were finally successfully treated with a conventional balloon. The combined permanent neurologic morbidity and mortality rate (stroke, ICH, and SAH) at 30 days was 1.6%. Substantial difference was found in the rate of recurrent stenosis when comparing conventional balloons and DEBs, with recurrent stenosis rates of 50% and 9%, respectively.

CONCLUSIONS

The initial results of reangioplasty of intracranial ISRs with DEBs are encouraging; further technical developments are, nevertheless, mandatory.

Recent studies have shown that, in mast cells, membrane microdomains rich in cholesterol and glycosphingolipids called lipid rafts play an important role in FcepsilonRI signaling. The present study demonstrates that, in RBL-2H3 cells following stimulation, the mast cell-specific gangliosides associated with FcepsilonRI are internalized from lipid rafts along with the receptor. When the cells are labeled with iodinated antibodies against the gangliosides or against FcepsilonRI and the cell components are then fractionated on Percoll density gradients, in stimulated cells the gangliosides are internalized with the same kinetics as FcepsilonRI and at 3 hr are present in the dense lysosome fraction. Using transmission electron microscopy, with antibody against the gangliosides conjugated to horseradish peroxidase and antibody against FcepsilonRI conjugated to colloidal gold, it was possible to demonstrate that the gangliosides and FcepsilonRI are internalized in the same coated vesicles. At 5 min, the gangliosides and FcepsilonRI can be identified in early endosomes and at 3 hr are found together in acid phosphatase-positive lysosomes. This study demonstrates that the mast cell-specific gangliosides are internalized from lipid rafts in the same vesicles and traffic intracellularly with the same kinetics as FcepsilonRI. This study contains online supplemental material at http://www.jhc.org. Please visit this article online to view these materials.

OBJECTIVE

To assess residents' difficulties during the first year of residency. In contrast to previous studies that mainly used structured questionnaires, a qualitative procedure was applied.

METHODS

Twenty-four consecutive first-year residents in internal medicine were asked to "Please identify two to three major difficulties or concerns related to your practice of medicine within this hospital". The answers were submitted to content analysis performed by three independent researchers. Inter-rater agreement was high (kappa coefficient = 0.92). Disagreements were solved by consensus.

RESULTS

Physicians' characteristics: female 37%, mean age 28 +/- 2.2 years, mean duration of postgraduate training 2.5 +/- 1.3 years. Total number of answers: 122, average answers/resident 5.1 +/- 1.3. Nine categories were extracted from content analysis: communication problems at the workplace, feelings of not being respected, constraints of collaborative work, experiencing the gap between medical school and clinical care, work overload, responsibility towards and emotional investment in patients, worries about career plans, and lack of theoretical knowledge. Residents expressed major difficulties in communicating with and being respected by seniors and peers in particular, and hospital staff in general. They also voiced problems in coping with emotions, either their own or those of their patients.

CONCLUSIONS

The residents' responses stressed the complexity of blending the requirements of the physician's role when instrumental/cognitive knowledge is not sufficient to deal with problems requiring personal and relational dimensions. Learning to combine medical knowledge and practice necessitates helping students/residents identify and deal with the constraints of these requirements.

Enhanced green fluorescent protein (GFP) irreversibly loses not only fluorescence but also antigenicity recognized with conventional anti-GFP antibodies by heat denaturation. This hinders combinatory applications of the GFP immunodetection technique with heat-requiring procedures, such as in situ hybridization histochemistry, antigen retrieval, and Western blot. Here we produced new rabbit and guinea pig antibodies against heat-denatured GFP. The polyclonal antibodies affinity-purified with the antigen column detected a single band corresponding to the molecular size of GFP in Western blot analysis, with mouse brain expressing GFP from the GAD67 locus. By immunofluorescence labeling, the new antibodies detected GFP molecules in heat >> or = 70 degrees C)-treated sections but not in untreated sections of the mouse brain. When the sections were incubated at>> or = 37 degrees C with in situ hybridization buffer containing 50% formamide, a denaturing reagent, the sections lost immunoreactivity with the conventional anti-GFP antibodies but acquired immunoreactivity with the new antibodies to heat-denatured GFP. Finally, GFP immunofluorescence was successfully visualized with the new antibodies in sections of the GFP-expressing mice labeled by fluorescence in situ hybridization histochemistry against GAD67 mRNA. Thus, the antibodies produced in this study may provide an opportunity to combine GFP immunodetection with procedures requiring heat treatment. This manuscript contains online supplemental material at http://www.jhc.org. Please visit this article online to view these materials.

BACKGROUND

Dementia is one of the most disabling and burdensome diseases. Incontinence in people with dementia is distressing, adds to carer burden, and influences decisions to relocate people to care homes. Successful and safe management of incontinence in people with dementia presents additional challenges. The aim of this study was to investigate the rates of first diagnosis in primary care of urinary and faecal incontinence among people aged 60-89 with dementia, and the use of medication or indwelling catheters for urinary incontinence.

RESULTS

We extracted data on 54,816 people aged 60-89 with dementia and an age-gender stratified sample of 205,795 people without dementia from 2001 to 2010 from The Health Improvement Network (THIN), a United Kingdom primary care database. THIN includes data on patients and primary care consultations but does not identify care home residents. Rate ratios were adjusted for age, sex, and co-morbidity using multilevel Poisson regression. The rates of first diagnosis per 1,000 person-years at risk (95% confidence interval) for urinary incontinence in the dementia cohort, among men and women, respectively, were 42.3 (40.9-43.8) and 33.5 (32.6-34.5). In the non-dementia cohort, the rates were 19.8 (19.4-20.3) and 18.6 (18.2-18.9). The rates of first diagnosis for faecal incontinence in the dementia cohort were 11.1 (10.4-11.9) and 10.1 (9.6-10.6). In the non-dementia cohort, the rates were 3.1 (2.9-3.3) and 3.6 (3.5-3.8). The adjusted rate ratio for first diagnosis of urinary incontinence was 3.2 (2.7-3.7) in men and 2.7 (2.3-3.2) in women, and for faecal incontinence was 6.0 (5.1-7.0) in men and 4.5 (3.8-5.2) in women. The adjusted rate ratio for pharmacological treatment of urinary incontinence was 2.2 (1.4-3.7) for both genders, and for indwelling urinary catheters was 1.6 (1.3-1.9) in men and 2.3 (1.9-2.8) in women.

CONCLUSIONS

Compared with those without a dementia diagnosis, those with a dementia diagnosis have approximately three times the rate of diagnosis of urinary incontinence, and more than four times the rate of faecal incontinence, in UK primary care. The clinical management of urinary incontinence in people with dementia with medication and particularly the increased use of catheters is concerning and requires further investigation. Please see later in the article for the Editors' Summary.

IAGG, WHO, and SFGG organized a international workshop on Health promotion programs on prevention of late on-set dementia. Thirty world specialists coming from Europe, North America, Asia, South America, Africa and Australia, shared their experience on methods and results of large epidemiological interventions to reduce incidents of dementia or delay its on-set. Chaired by Laura FRATIGLIONI, an expert in Epidemiological studies on dementia issues, the workshop gave opportunity for discussions and controversies about the state-of-the-art. Based on different national and international trials (ADAPT, MAPT, FINGER, GUDIAGE, GEM etc) the questions remained opened for different aspects of methodology, the choice of domain or multi domain intervention, the choice and the definition of the target populations, the best age of candidates, the issues related to the discrepancy between late effects, and interventions' duration. We are please to publish in the Journal, the presentations presented to this workshop. These publications will complete previously task force published in the journal in the last two years on methodological issues for Alzheimer's trials including end point, biomarkers, and the experience of past therapeutic trials.

BACKGROUND

Over the last four decades, various urinary FSH (uFSH) products of different purity have been developed. In 1988 recombinant FSH (rFSH ) was prepared by transfecting Chinese hamster ovary cell lines with both FSH subunit genes. Both rFSH and uFSH are known to be effective in inducing ovulation in women with clomiphene-resistant polycystic ovary syndrome. Ovulation induction with FSH bears the risk of multiple follicle development, multiple pregnancies and ovarian hyperstimulation syndrome. The dose regimen used can affect the incidence of these complications.

OBJECTIVE

To compare in women with clomiphene-resistant polycystic ovary syndrome (PCOS) the safety and effectiveness in terms of ovulation, pregnancy, miscarriage, multiple pregnancy rate and ovarian hyperstimulation syndrome (OHSS) of 1) rFSH with uFSH and 2) different dose regimens of rFSH.

METHODS

The search strategy of the Menstrual Disorders and Subfertility review group was used to identify all relevant trials. Please see Review Group details.

METHODS

All relevant published RCT's were selected. Randomised controlled trials were eligible for inclusion if treatment consisted of recombinant FSH versus urinary FSH or recombinant FSH in different dose regimens, to induce ovulation in subfertile women with PCOS.

METHODS

A computerised MEDLINE and EMBASE search was used to identify randomised and non randomised controlled trials. The reference lists of all studies found were checked for relevant articles. Handsearching of bibliographies of relevant publications and reviews and abstracts of scientific meetings was performed. Serono Benelux BV and NV Organon, the manufacturers of follitropin alpha (Gonal F(R)) and follitropin beta (Puregon(R)) respectively, were asked for unpublished data and ongoing studies. Relevant data were extracted independently by two reviewers (NB, MW). Validity was assessed in terms of method of randomisation, completeness of follow-up, presence or absence of cross-over and co-intervention. All trials were screened and analysed according to predetermined quality criteria.

RESULTS

2X2 tables were generated for all the relevant outcomes. Odds ratios were generated using the Peto modified Mantel-Haenszel technique.

RESULTS

Four randomised trials comparing rFSH versus uFSH were identified. No significant differences were demonstrated for the relevant outcomes. The odds ratio for ovulation rate was 1.19 (95% CI 0.78,1.80), for pregnancy rate 0.95 (95% CI 0.64,1.41), for miscarriage rate 1.26 (95% CI 0.59,2.70), for multiple pregnancy rate 0.44 (95% CI 0.16,1.21) and for OHSS 1.55 (95% CI 0.50,4.84). Similarly, in the only randomised trial that compared chronic low dose versus conventional regimen with rFSH no significant differences were found.

CONCLUSIONS

At this moment there are not sufficient data to determine which of rFSH or uFSH is preferable for ovulation induction in women with PCOS.

Hilda Bastian considers post-publication commenting and the cultural changes that are needed to better capture this intellectual effort. Please see later in the article for the Editors' Summary.

BACKGROUND

Pateclizumab (MLTA3698A) is a humanized mAb against lymphotoxin α (LTα), a transiently expressed cytokine on activated B and T cells (Th1, Th17), which are implicated in rheumatoid arthritis (RA) pathogenesis. This study was conducted to assess the safety, tolerability, < NOTE: For clarity and per AMA/S-W Style, please restore the use of Oxford/serial commas (ie: David likes vanilla, strawberry, and chocolate ice cream) throughout. and biologic activity of single and multiple doses of intravenous (IV) or subcutaneous (SC) pateclizumab in RA patients.

METHODS

The single ascending dose (SAD) phase in patients with stable RA consisted of six cohorts (4:1 active:placebo at 0.3 mg/kg IV, 1.0 mg/kg IV, 1.0 mg/kg SC, 3.0 mg/kg IV, 3.0 mg/kg SC, and 5.0 mg/kg IV; n = 5/cohort). In the multiple ascending dose (MAD) phase, patients with prespecified RA disease activity received three doses of pateclizumab or placebo (4:1) every 2 weeks (1.0 mg/kg SC, n = 10; 3.0 mg/kg SC, n = 20; or 5.0 mg/kg IV, n = 5). Safety and tolerability were assessed throughout, and clinical activity was determined after three doses (Week 6).

RESULTS

We observed no serious adverse events (AEs) or dose-limiting toxicities, and the majority of AEs were mild to moderate. The pharmacokinetic profiles were linear, and clearance was independent of dose. Reductions in levels of serum CXCL13 were observed, supporting the biologic activity of pateclizumab on the LTα pathway. Patients receiving pateclizumab in the 3.0 mg/kg MAD group (3.0 mg/kg SC) demonstrated ACR20, ACR50, and ACR70 response rates at week 6 of 75%, 56% and 25%, respectively, compared with 57%, 29%, and 0% in the placebo group. The median Disease Activity Score in 28 joints, C-reactive protein, reduction was 28% for pateclizumab, versus 8.4% for placebo.

CONCLUSIONS

Pateclizumabwas generally well-tolerated in RA patients. Preliminary evidence of clinical activity was observed in active RA patients at the dose level targeted for clinical effect.

OBJECTIVE

To examine Australian smokers' attitudes towards regulation of the tobacco industry and to compare their attitudes with those of three similar countries--the United Kingdom (UK), the United States (US), and Canada.

METHODS

A telephone survey of 2,056 adult Australian smokers and 6,166 Canadian, US, and UK smokers was conducted in 2004 as the third wave of the International Tobacco Control Policy Evaluation Four-Country Survey.

RESULTS

Australian smokers display the strongest support for regulation. Only 16% believe that tobacco companies should be allowed to advertise/promote cigarettes as they please, 70% agree that tobacco products should be more tightly regulated, and 64% agree that governments should do more to tackle the harms of smoking. Smokers see government failure to do so in cynical terms -77% agree that governments do not really care about smoking because of money from tobacco taxes. Opposition comes largely from smokers who hold self-exempting beliefs about smoking's risks, have a positive attitude to smoking, do not accept that smoking is socially denormalised, and do not hold tobacco companies responsible for harms caused by smoking.

CONCLUSIONS

The majority of Australian smokers believe that the tobacco industry is partly responsible for the predicament they find themselves in and want governments to act more strongly in their real interests. The strong relationship between support for regulation and cynicism about government inaction should stimulate governments into action.

RNA-binding proteins (RBPs) are essential players in RNA metabolism including key cellular processes from pre-mRNA splicing to mRNA translation. The K homology-type QUAKING RBP is emerging as a vital factor for oligodendrocytes, monocytes/macrophages, endothelial cell, and myocyte function. Interestingly, the qkI gene has now been identified as the culprit gene for a patient with intellectual disabilities and is translocated in a pediatric ganglioglioma as a fusion protein with MYB. In this review, we will focus on the emerging discoveries of the QKI proteins as well as highlight the recent advances in understanding the role of QKI in human disease pathology including myelin disorders, schizophrenia and cancer. WIREs RNA 2016, 7:399-412. doi: 10.1002/wrna.1344 For further resources related to this article, please visit the WIREs website.

Gestational diabetes mellitus (GDM) is associated with short- and long-term complications for the mother and her infant. Women who are unable to maintain their blood glucose concentration within pre-specified treatment targets with diet and lifestyle interventions will require anti-diabetic pharmacological therapies. This review explores the safety and effectiveness of insulin compared with oral anti-diabetic pharmacological therapies, non-pharmacological interventions and insulin regimens.

To evaluate the effects of insulin in treating women with gestational diabetes.

We searched Pregnancy and Childbirth's Trials Register (1 May 2017), ClinicalTrials.gov, WHO International Clinical Trials Registry Platform (ICTRP) (1 May 2017) and reference lists of retrieved studies.

We included randomised controlled trials (including those published in abstract form) comparing:a) insulin with an oral anti-diabetic pharmacological therapy;b) with a non-pharmacological intervention;c) different insulin analogues;d) different insulin regimens for treating women with diagnosed with GDM.We excluded quasi-randomised and trials including women with pre-existing type 1 or type 2 diabetes. Cross-over trials were not eligible for inclusion.

Two review authors independently assessed study eligibility, risk of bias, and extracted data. Data were checked for accuracy.

We included 53 relevant studies (103 publications), reporting data for 7381 women. Forty-six of these studies reported data for 6435 infants but our analyses were based on fewer number of studies/participants.Overall, the risk of bias was unclear; 40 of the 53 included trials were not blinded. Overall, the quality of the evidence ranged from moderate to very low quality. The primary reasons for downgrading evidence were imprecision, risk of bias and inconsistency. We report the results for our maternal and infant GRADE outcomes for the main comparison. Insulin versus oral anti-diabetic pharmacological therapyFor the mother, insulin was associated with an increased risk for hypertensive disorders of pregnancy (not defined) compared to oral anti-diabetic pharmacological therapy (risk ratio (RR) 1.89, 95% confidence interval (CI) 1.14 to 3.12; four studies, 1214 women; moderate-quality evidence). There was no clear evidence of a difference between those who had been treated with insulin and those who had been treated with an oral anti-diabetic pharmacological therapy for the risk of pre-eclampsia (RR 1.14, 95% CI 0.86 to 1.52; 10 studies, 2060 women; moderate-quality evidence); the risk of birth by caesarean section (RR 1.03, 95% CI 0.93 to 1.14; 17 studies, 1988 women; moderate-quality evidence); or the risk of developing type 2 diabetes (metformin only) (RR 1.39, 95% CI 0.80 to 2.44; two studies, 754 women; moderate-quality evidence). The risk of undergoing induction of labour for those treated with insulin compared with oral anti-diabetic pharmacological therapy may possibly be increased, although the evidence was not clear (average RR 1.30, 95% CI 0.96 to 1.75; three studies, 348 women; I² = 32%; moderate-quality of evidence). There was no clear evidence of difference in postnatal weight retention between women treated with insulin and those treated with oral anti-diabetic pharmacological therapy (metformin) at six to eight weeks postpartum (MD -1.60 kg, 95% CI -6.34 to 3.14; one study, 167 women; low-quality evidence) or one year postpartum (MD -3.70, 95% CI -8.50 to 1.10; one study, 176 women; low-quality evidence). The outcomes of perineal trauma/tearing or postnatal depression were not reported in the included studies.For the infant, there was no evidence of a clear difference between those whose mothers had been treated with insulin and those treated with oral anti-diabetic pharmacological therapies for the risk of being born large-for-gestational age (average RR 1.01, 95% CI 0.76 to 1.35; 13 studies, 2352 infants; moderate-quality evidence); the risk of perinatal (fetal and neonatal death) mortality (RR 0.85; 95% CI 0.29 to 2.49; 10 studies, 1463 infants; low-quality evidence);, for the risk of death or serious morbidity composite (RR 1.03, 95% CI 0.84 to 1.26; two studies, 760 infants; moderate-quality evidence); the risk of neonatal hypoglycaemia (average RR 1.14, 95% CI 0.85 to 1.52; 24 studies, 3892 infants; low-quality evidence); neonatal adiposity at birth (% fat mass) (mean difference (MD) 1.6%, 95% CI -3.77 to 0.57; one study, 82 infants; moderate-quality evidence); neonatal adiposity at birth (skinfold sum/mm) (MD 0.8 mm, 95% CI -2.33 to 0.73; random-effects; one study, 82 infants; very low-quality evidence); or childhood adiposity (total percentage fat mass) (MD 0.5%; 95% CI -0.49 to 1.49; one study, 318 children; low-quality evidence). Low-quality evidence also found no clear differences between groups for rates of neurosensory disabilities in later childhood: hearing impairment (RR 0.31, 95% CI 0.01 to 7.49; one study, 93 children), visual impairment (RR 0.31, 95% CI 0.03 to 2.90; one study, 93 children), or any mild developmental delay (RR 1.07, 95% CI 0.33 to 3.44; one study, 93 children). Later infant mortality, and childhood diabetes were not reported as outcomes in the included studies.We also looked at comparisons for regular human insulin versus other insulin analogues, insulin versus diet/standard care, insulin versus exercise and comparisons of insulin regimens, however there was insufficient evidence to determine any differences for many of the key health outcomes. Please refer to the main results for more information about these comparisons.

The main comparison in this review is insulin versus oral anti-diabetic pharmacological therapies. Insulin and oral anti-diabetic pharmacological therapies have similar effects on key health outcomes. The quality of the evidence ranged from very low to moderate, with downgrading decisions due to imprecision, risk of bias and inconsistency.For the other comparisons of this review (insulin compared with non-pharmacological interventions, different insulin analogies or different insulin regimens), there is insufficient volume of high-quality evidence to determine differences for key health outcomes.Long-term maternal and neonatal outcomes were poorly reported for all comparisons.The evidence suggests that there are minimal harms associated with the effects of treatment with either insulin or oral anti-diabetic pharmacological therapies. The choice to use one or the other may be down to physician or maternal preference, availability or severity of GDM. Further research is needed to explore optimal insulin regimens. Further research could aim to report data for standardised GDM outcomes.

Prions are proteinaceous particles that propagate alternative protein conformations/states to further copies of the same proteins, and are transmitted from cell-to-cell, and organism-to-organism. Prions are usually made of the beta-sheet rich assemblies termed amyloid. The original prion protein PrP causes devastating neurodegenerative disorders in humans and other mammals. In the yeast Saccharomyces cerevisiae, many prion-forming proteins have been observed; a prominent feature of these proteins is an intrinsically disordered domain rich in glutamine (Q) and asparagine (N) residues. Several human proteins that are yeast-prion-like, in particular those with poly-glutamine (poly-Q) expansions, have been experimentally implicated in human neurodegenerative diseases.

Here, we have constructed a comprehensive list of human yeast-prion-like proteins that are linked to human neurological disease. Surprisingly, different methods to annotate yeast-prion-like proteins in humans have limited intersection. However, independent of annotation method, we find that human yeast-prion-like proteins as a group have a statistically significant genetic linkage to neurological disease, that is caused specifically by linkage to neurodegenerative diseases. This is despite: (i) no especially high expression of yeast-prion-like proteins in the central nervous system, or (ii) no general enrichment of intrinsically disordered proteins in neurological/neurodegenerative diseases. Cytoskeletal proteins are significantly overrepresented in the set of human yeast-prion-like neurological proteins. Whether involved in neurological pathomechanisms or not, yeast-prion-like proteins in humans have very limited conservation outside of Deuterostomia (< ~10 %) with only a handful having prion-like character in both human and S. cerevisiae. The only such protein with a disease linkage is PUB1/TIA1, which functions as a stress granule component. Thus, the yeast-prion-like character of proteins linked to neurodegenerative diseases has not been conserved over the deep evolutionary time since the last common ancestor of yeasts and humans.

Our results provide a comprehensive picture of yeast-prion-like proteins in humans and contribute to the strategic basis for experimental investigation of the link between yeast-prion-like protein character and neurological disease.

Reviewed by Istvan Simon and Alexander Schleiffer. For the full reviews, please go to the Reviewers' comments section.

BACKGROUND

WHO recommends prompt diagnosis and quinine plus clindamycin for treatment of uncomplicated malaria in the first trimester and artemisinin-based combination therapies in subsequent trimesters. We undertook a systematic review of women's access to and healthcare provider adherence to WHO case management policy for malaria in pregnant women.

RESULTS

We searched the Malaria in Pregnancy Library, the Global Health Database, and the International Network for the Rational Use of Drugs Bibliography from 1 January 2006 to 3 April 2014, without language restriction. Data were appraised for quality and content. Frequencies of women's and healthcare providers' practices were explored using narrative synthesis and random effect meta-analysis. Barriers to women's access and providers' adherence to policy were explored by content analysis using NVivo. Determinants of women's access and providers' case management practices were extracted and compared across studies. We did not perform a meta-ethnography. Thirty-seven studies were included, conducted in Africa (30), Asia (4), Yemen (1), and Brazil (2). One- to three-quarters of women reported malaria episodes during pregnancy, of whom treatment was sought by >85%. Barriers to access among women included poor knowledge of drug safety, prohibitive costs, and self-treatment practices, used by 5%-40% of women. Determinants of women's treatment-seeking behaviour were education and previous experience of miscarriage and antenatal care. Healthcare provider reliance on clinical diagnosis and poor adherence to treatment policy, especially in first versus other trimesters (28%, 95% CI 14%-47%, versus 72%, 95% CI 39%-91%, p = 0.02), was consistently reported. Prescribing practices were driven by concerns over side effects and drug safety, patient preference, drug availability, and cost. Determinants of provider practices were access to training and facility type (public versus private). Findings were limited by the availability, quality, scope, and methodological inconsistencies of the included studies.

CONCLUSIONS

A systematic assessment of the extent of substandard case management practices of malaria in pregnancy is required, as well as quality improvement interventions that reach all providers administering antimalarial drugs in the community. Pregnant women need access to information on which anti-malarial drugs are safe to use at different stages of pregnancy. Please see later in the article for the Editors' Summary.

The GT dinucleotide in the first two intron positions is the most conserved element of the U2 donor splice signals. However, in a small fraction of donor sites, GT is replaced by GC. A substantial enrichment of GC in donor sites of alternatively spliced genes has been observed previously in human, nematode and Arabidopsis, suggesting that GC signals are important for regulation of alternative splicing. We used parsimony analysis to reconstruct evolution of donor splice sites and inferred 298 GT>> GC conversion events compared to 40 GC>> GT conversion events in primate and rodent genomes. Thus, there was substantive accumulation of GC donor splice sites during the evolution of mammals. Accumulation of GC sites might have been driven by selection for alternative splicing.

METHODS

This article was reviewed by Jerzy Jurka and Anton Nekrutenko. For the full reviews, please go to the Reviewers' Reports section.

Theory of mind and its development has been a significantly important-and challenging-topic of research in cognitive science for three decades. This review summarizes our knowledge of when and how children come to understand their own and others' minds, including the developmental timetable, old and new measures, and foundational skills in infancy. We review recent research on theory-of-mind (ToM) and learning, that is, ways in which children's understanding of other minds informs how they learn about the world, as well as evidence for an important role of domain-general cognitive skills (executive function) in the development of ToM, and the neural networks that are most strongly implicated. Finally, we propose future directions for research in this vast and growing field. WIREs Cogn Sci 2013, 4:391-402. doi: 10.1002/wcs.1232 The authors have declared no conflicts of interest for this article. For further resources related to this article, please visit the WIREs website.

Highly conserved noncoding RNA (ncRNA) elements in viral genomes and transcripts offer new opportunities to expand the repertoire of drug targets for the development of antiinfective therapy. Ligands binding to ncRNA architectures are able to affect interactions, structural stability or conformational changes and thereby block processes essential for viral replication. Proof of concept for targeting functional RNA by small molecule inhibitors has been demonstrated for multiple viruses with RNA genomes. Strategies to identify antiviral compounds as inhibitors of ncRNA are increasingly emphasizing consideration of drug-like properties of candidate molecules emerging from screening and ligand design. Recent efforts of antiviral lead discovery for RNA targets have provided drug-like small molecules that inhibit viral replication and include inhibitors of human immunodeficiency virus (HIV), hepatitis C virus (HCV), severe respiratory syndrome coronavirus (SARS CoV), and influenza A virus. While target selectivity remains a challenge for the discovery of useful RNA-binding compounds, a better understanding is emerging of properties that define RNA targets amenable for inhibition by small molecule ligands. Insight from successful approaches of targeting viral ncRNA in HIV, HCV, SARS CoV, and influenza A will provide a basis for the future exploration of RNA targets for therapeutic intervention in other viral pathogens which create urgent, unmet medical needs. Viruses for which targeting ncRNA components in the genome or transcripts may be promising include insect-borne flaviviruses (Dengue, Zika, and West Nile) and filoviruses (Ebola and Marburg). WIREs RNA 2016, 7:726-743. doi: 10.1002/wrna.1373 For further resources related to this article, please visit the WIREs website.